Approximately 8% of the genomes of mammals, including humans and mice, are comprised of retroviral elements acquired by infection of germ line cells during the course of evolution. Retroviral insertions in our genome number about 40,000 and are in the same range as the total number of genes encoded by our DNA. Many endogenous retrovirus elements are defective, however some appear to be intact, and several contain one or more viral genes that are expressed during development and certain physiological or pathological conditions. Little is known about the control of retrovirus expression or the influence of such expression on the physiology or pathology of the host. An extensively investigated group of endogenous retroviruses are those giving rise to polytropic murine leukemia viruses (MuLVs) in mice. In several instances polytropic MuLVs have been directly implicated in pathogenesis, including the induction of proliferative, immunological, and neurological disorders. Polytropic MuLVs are formed by recombination of exogenous ecotropic MuLVs with endogenous envelope sequences present in the genomes of inbred mouse strains and their generation results in a mixed retrovirus infection. We have investigated the interactions of retroviruses in mixed infections in vivo by co-inoculation of mice with polytropic and ecotropic MuLVs and observed remarkable alterations in the types and tempo of disease induced by different mixtures of viruses. These included a highly significant delay in the induction of proliferative disease with one polytropic MuLV and a profound synergistic effect resulting in the abrupt development of a neurological disease with another polytropic isolate. In the first case the delay in disease induction correlated with in vivo retroviral interference resulting in the suppression the generation of new polytropic MuLVs normally observed after infection with the exogenous ecotropic MuLV. The rapid development of neurological disease were accompanied by extensive pseudotyping of the polytropic MuLV genome within ecotropic virions and a striking elevation of polytropic MuLV infection and replication in co-inoculated mice. [unreadable] Another aspect of our studies involves the characterization of the family of endogenous retroviruses that participate in recombination to yield polytropic MuLVs. Structural studies of these endogenous viruses suggest that they have undergone recent periods of active replication. We have found that mice infected with exogenous retroviruses release infectious virus particles containing RNA sequences corresponding to complete transcripts of the endogenous proviruses. At early times after infection with the Friend MuLV, packaging and transfer of intact endogenous retroviruses is much more prevalent than recombination. The mobilization of intact endogenous retroviruses is unprecedented and may have important implications for the involvement of endogenous retroviruses in disease processes.